EP0296040A1 - Dérivés de l'actinonine doués d'activités physiologiques - Google Patents
Dérivés de l'actinonine doués d'activités physiologiques Download PDFInfo
- Publication number
- EP0296040A1 EP0296040A1 EP88401437A EP88401437A EP0296040A1 EP 0296040 A1 EP0296040 A1 EP 0296040A1 EP 88401437 A EP88401437 A EP 88401437A EP 88401437 A EP88401437 A EP 88401437A EP 0296040 A1 EP0296040 A1 EP 0296040A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- actinonin
- compound
- amnesia
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- XJLATMLVMSFZBN-VYDXJSESSA-N actinonin Chemical class CCCCC[C@H](CC(=O)NO)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1CO XJLATMLVMSFZBN-VYDXJSESSA-N 0.000 title claims abstract description 69
- 230000001766 physiological effect Effects 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 102
- 208000000044 Amnesia Diseases 0.000 claims abstract description 26
- 208000031091 Amnestic disease Diseases 0.000 claims abstract description 26
- 230000006986 amnesia Effects 0.000 claims abstract description 26
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 15
- 241001465754 Metazoa Species 0.000 claims abstract description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- XJLATMLVMSFZBN-UHFFFAOYSA-N actinonine Natural products CCCCCC(CC(=O)NO)C(=O)NC(C(C)C)C(=O)N1CCCC1CO XJLATMLVMSFZBN-UHFFFAOYSA-N 0.000 claims description 52
- 238000000034 method Methods 0.000 claims description 21
- -1 alkali metal periodate Chemical class 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 230000008569 process Effects 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 230000001590 oxidative effect Effects 0.000 claims description 8
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 6
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- HVVNJUAVDAZWCB-YFKPBYRVSA-N [(2s)-pyrrolidin-2-yl]methanol Chemical group OC[C@@H]1CCCN1 HVVNJUAVDAZWCB-YFKPBYRVSA-N 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 5
- 229940124597 therapeutic agent Drugs 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 26
- 241000699670 Mus sp. Species 0.000 abstract description 16
- YPHMISFOHDHNIV-FSZOTQKASA-N cycloheximide Chemical compound C1[C@@H](C)C[C@H](C)C(=O)[C@@H]1[C@H](O)CC1CC(=O)NC(=O)C1 YPHMISFOHDHNIV-FSZOTQKASA-N 0.000 abstract description 16
- 102000035195 Peptidases Human genes 0.000 abstract description 9
- 108091005804 Peptidases Proteins 0.000 abstract description 9
- 235000019833 protease Nutrition 0.000 abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 abstract 1
- 239000001257 hydrogen Substances 0.000 abstract 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 238000012360 testing method Methods 0.000 description 14
- 102000004190 Enzymes Human genes 0.000 description 13
- 108090000790 Enzymes Proteins 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 241000699666 Mus <mouse, genus> Species 0.000 description 12
- 102000056251 Prolyl Oligopeptidases Human genes 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 101710178372 Prolyl endopeptidase Proteins 0.000 description 11
- 101710129873 Prolyl endopeptidase FAP Proteins 0.000 description 11
- 230000001225 therapeutic effect Effects 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 7
- 230000000844 anti-bacterial effect Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000011835 investigation Methods 0.000 description 5
- 230000002503 metabolic effect Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 230000032050 esterification Effects 0.000 description 4
- 238000005886 esterification reaction Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 244000005700 microbiome Species 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide-pyridine complex Substances O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 150000003443 succinic acid derivatives Chemical class 0.000 description 3
- 241000186361 Actinobacteria <class> Species 0.000 description 2
- 229940122344 Peptidase inhibitor Drugs 0.000 description 2
- 241000187747 Streptomyces Species 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000007385 chemical modification Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000003407 synthetizing effect Effects 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 1
- SGMBVPIPMLDJJJ-LEKXZLICSA-N 3-[(2S)-1-[(2S)-2-amino-3-methylbutanoyl]-2-formylpyrrolidine-2-carbonyl]octanoic acid Chemical compound C(CCCC)C(C(=O)[C@@]1(N(CCC1)C([C@@H](N)C(C)C)=O)C=O)CC(=O)O SGMBVPIPMLDJJJ-LEKXZLICSA-N 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- 208000032274 Encephalopathy Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- UTXSFKPOIVELPQ-SFHVURJKSA-N benzyl n-[2-[(2s)-2-[(4-nitrophenyl)carbamoyl]pyrrolidin-1-yl]-2-oxoethyl]carbamate Chemical compound C1=CC([N+](=O)[O-])=CC=C1NC(=O)[C@H]1N(C(=O)CNC(=O)OCC=2C=CC=CC=2)CCC1 UTXSFKPOIVELPQ-SFHVURJKSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000002434 immunopotentiative effect Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Definitions
- an actionin derivative represented by the general formula (I): wherein R means a hydrogen atom or a lower alkyl group.
- the compound of the formula (I) shows the therapeutic effects to therapeutically treat an experimental amnesia in mice.
- such compounds having the enzyme-inhibitory activity against PPCE have been studied as therapeutic drugs for various encephalopathy.
- the therapeutic effects of compounds for the amnesia can be tested in regard to the therapeutic effects of compounds for an experimental amnesia in mice which has been induced by administration of cycloheximide to mice.
- the compounds of the general formula (I), including the compound of the formula (Ia) shown below and the compounds of the formula (I′) shown below may be produced by such processes comprising the reaction steps as depicted by the following reaction schemes A and B.
- an actinonin derivative of the formula (Ia) which comprises reacting actinonin of the formula (II) with an alkali metal periodate to remove the hydroxyamino group from the actinonin and thereby to give a compound of the formula (III) and then oxidizing the hydroxymethyl group of the prolinol moiety of the compound of the formula (III) into the formyl group to produce the compound of the formula (Ia).
- the compounds of the formulae (III) and (IV) which are produced as the intermediate products in the above processes are new compounds and are useful for the production of the actinonin-related compounds of the general formula (I) and also possibly for the synthetic production of any other actinonin-related compounds.
- the compounds of the formulae (III) and (IV) may be represented by the following general formula (VI) wherein R means a hydrogen atom or a lower alkyl group.
- actinonin derivative of the formula (I) according to this invention when used as a therapeutic agent for treatment of amnesia, it may be formulated into various forms such as powder, tablet, capsule, injectionable solution or suspension, by mixing with a pharmaceutically acceptable solid or liquid carrier as usually known in the pharmaceutical field.
- Actinonin 1.0 g was suspended in water (100 ml), followed by addition of 15N aqueous sodium periodate (25 ml) to resulting aqueous suspension of actinonin. The suspension was then stirred overnight at room temperature so as to conduct the dehydroxyamination reaction, whereby the hydroxyamino group was removed from the actinonin molecule.
- the reaction mixture obtained was saturated with sodium chloride and then extracted with ethyl ether (100 ml).
- the resulting ethyl ether layer ie., the extract solution
- the aqueous phases (the extract solutions) thus obtained were combined together and adjusted to pH 2 with 1N HCl.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- General Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Psychiatry (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hospice & Palliative Care (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP144176/87 | 1987-06-11 | ||
| JP62144176A JPH0774194B2 (ja) | 1987-06-11 | 1987-06-11 | 生理活性を有する新規なアクチノニン誘導体 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0296040A1 true EP0296040A1 (fr) | 1988-12-21 |
| EP0296040B1 EP0296040B1 (fr) | 1993-04-28 |
Family
ID=15355973
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP88401437A Expired - Lifetime EP0296040B1 (fr) | 1987-06-11 | 1988-06-10 | Dérivés de l'actinonine doués d'activités physiologiques |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US4929633A (fr) |
| EP (1) | EP0296040B1 (fr) |
| JP (1) | JPH0774194B2 (fr) |
| DE (1) | DE3880561T2 (fr) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0468469A2 (fr) * | 1990-07-27 | 1992-01-29 | Japan Tobacco Inc. | Dérivés de proline |
| EP0474553A1 (fr) * | 1990-09-04 | 1992-03-11 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Dérivés de l'actinonine |
| US5506256A (en) * | 1990-07-27 | 1996-04-09 | Yoshitomi Pharmaceutical Industries, Ltd. | Proline derivatives possessing prolyl endopeptidase-inhibitory activity |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2691442B2 (ja) * | 1989-02-20 | 1997-12-17 | 株式会社ヤクルト本社 | 新規なプロリン誘導体 |
| US5049578A (en) * | 1990-03-09 | 1991-09-17 | E. R. Squibb & Sons, Inc. | 1-aroyl or 1-acyl-2-2pyrrolidinyl-3,5-dihydroxy alkanoic and alkenoic acids, salts, esters and lactones |
| US5298627A (en) * | 1993-03-03 | 1994-03-29 | Warner-Lambert Company | Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis |
| DE10100053A1 (de) * | 2001-01-02 | 2002-08-22 | Keyneurotek Ag I G | Verwendung von Enzyminhibitoren der Dipeptidylpeptidase IV sowie der Aminopeptidase N und pharmazeutischen Zubereitungen daraus zur Prävention und/oder Therapie Ischämie-bedingter akuter und chronischer neurodegenerativer Prozesse und Erkrankungen |
| JP2004532826A (ja) * | 2001-03-19 | 2004-10-28 | スローン−ケッタリング インスティトゥート フォー カンサー リサーチ | （ｓ，ｒ，ｒ）−（−）−アクチノニンおよびそのアナログの不斉合成、ならびにそれらの使用 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3240787A (en) * | 1962-01-23 | 1966-03-15 | Inst Medical Res | Alpha-hydroxymethyl-n-[omega-hydroxamic-acid-ethylene-carbonylamino-methylene-carbonyl]-pyrrolidine and process for its production |
| US4663342A (en) * | 1984-07-03 | 1987-05-05 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Pharmaceutical composition and method for immunopotentiation |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6137764A (ja) * | 1984-07-31 | 1986-02-22 | Suntory Ltd | 抗プロリルエンドペプチダ−ゼ活性を有する新規生理活性化合物 |
| JPH0623190B2 (ja) * | 1985-04-16 | 1994-03-30 | サントリー株式会社 | インヒビタ−活性を有するｎ−アシルピロリジン誘導体及びその製法並びに用途 |
-
1987
- 1987-06-11 JP JP62144176A patent/JPH0774194B2/ja not_active Expired - Lifetime
-
1988
- 1988-06-08 US US07/203,888 patent/US4929633A/en not_active Expired - Fee Related
- 1988-06-10 EP EP88401437A patent/EP0296040B1/fr not_active Expired - Lifetime
- 1988-06-10 DE DE88401437T patent/DE3880561T2/de not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3240787A (en) * | 1962-01-23 | 1966-03-15 | Inst Medical Res | Alpha-hydroxymethyl-n-[omega-hydroxamic-acid-ethylene-carbonylamino-methylene-carbonyl]-pyrrolidine and process for its production |
| US4663342A (en) * | 1984-07-03 | 1987-05-05 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Pharmaceutical composition and method for immunopotentiation |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0468469A2 (fr) * | 1990-07-27 | 1992-01-29 | Japan Tobacco Inc. | Dérivés de proline |
| EP0468469A3 (fr) * | 1990-07-27 | 1994-01-19 | Japan Tobacco Inc | |
| US5506256A (en) * | 1990-07-27 | 1996-04-09 | Yoshitomi Pharmaceutical Industries, Ltd. | Proline derivatives possessing prolyl endopeptidase-inhibitory activity |
| EP0474553A1 (fr) * | 1990-09-04 | 1992-03-11 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Dérivés de l'actinonine |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0774194B2 (ja) | 1995-08-09 |
| DE3880561T2 (de) | 1993-09-30 |
| US4929633A (en) | 1990-05-29 |
| JPS63310864A (ja) | 1988-12-19 |
| EP0296040B1 (fr) | 1993-04-28 |
| DE3880561D1 (de) | 1993-06-03 |
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